Axons in the peripheral nervous system (PNS) spontaneously regenerate, allowing functional recovery after injury, which is largely absent in adult mammalian central nervous system. Intra- axonal protein synthesis is a key component of spontaneous regenerative responses in the PNS and this can be drastically enhanced in nerves that have been pre-conditioned by a prior injury. Our work has shown selective localization and differential translation of many axonal mRNAs in adult sensory neurons and axons of peripheral nerves. However, it is still not clear how translation of axonal mRNAs is regulated. Our long-term goal of this research is to understand the molecular mechanisms that provide spatial and temporal regulation for intra-axonal protein synthesis. Small non-coding RNAs (sncRNAs) have emerged as key controllers of gene expression in the nervous system. Among these, PIWI-interacting RNAs (piRNAs) are primarily known for their roles in silencing transposable elements in germline cells. Recently, piRNAs are suggested to contribute to neuronal development and function. However, the possibility that the piRNAs are acting locally within neuronal processes to regulate axonal mRNA translation has not been tested. We anticipate that axonal piRNAs could confer a unique advantage for coordinately altering the population of proteins generated in growth cones by targeting mRNA cohorts. Our preliminary work shows that piRNA-like small RNAs (piLRNAs) are present in axons of sciatic nerve and that depletion of MIWI protein, a murine homolog of PIWI, increases axon growth and decreases axon retraction after injury. In this proposal, we hypothesize that the MIWI protein and specific piLRNAs are selectively enriched in axons of neurons and are functionally important for neuronal morphology including axon growth and regeneration following injury. In Aim 1, we will determine whether piLRNAs are selectively enriched in axons of neuronal cells by directly contrasting levels of piLRNAs in axon vs. cell body compartment. In Aim 2, we will focus on piLRNAs-5567, 1199, 5901, 5598, and 5595 to examine whether these axonally enriched piLRNAs control axon growth and/or regeneration. Once completed, we will, for the first time, demonstrate the localization of neuronal piLRNAs in the axon compartment, and identify novel roles of the axonally enriched piLRNAs in sensory neurons in axon growth and/or regeneration.